The preferred route for the administration of most drugs is via the gastrointestinal tract Most drugs are well absorbed from throughout the entire intestinal tract, but some compounds, usually those which are polar in nature, are poorly absorbed from the large intestine. For such drugs, the main area from which absorption occurs is the small intestine. Some drugs may exploit a natural pathway, such as receptor-mediated transport, active transport or other specific transport mechanisms, and are known to have socalled "absorption windows" in the small intestine. The term "absorption windows" describes the fact that a drug will be absorbed from a limited region of the intestine rather than the whole of the small and large intestines. The "window" could represent the duodenum, the jejunum or the ileum or parts thereof. Examples of such drugs include methyldopa and captopril. It would be advantageous to hold these drugs, which may display less than ideal absorption behaviour from the small intestine, in the stomach above their main absorption site for extended time periods, for example by way of a gastroretentive drug formulation.
A gastroretentive system would also be of value in the administration of a drug which is intended to produce a local effect in the stomach. A good example of this type of therapy is provided by way of the w ell known use of antibiotics in the local treatment of Helicobacter pylori (H. pylori) Furthermore, the use of antimicrobial substances for the treatment of Camplobacter pylori (with the additional treatment with other substances sach as H.sub.2 -receptor blockers) is suggested in an article by Hirsche and Pletschelte (1989) (Campylobacter pylori and Gastroduodenal Ulcers Rathbone and Heatley, eds.), Blackwell (1989) p. 217). More particularly, these authors also suggest that, if retention in the stomach could be achieved, drugs which demonstrate topical activity could be readily administered orally for local treatment.
Various methods have been proposed in the prior art to achieve gastroretention, including dosage forms which display extended residence in the stomach due to their density or size, or through the use of mechanisms based on a putative bioadhesion concept.
The topic of gastroretentive dosage forms has been well reviewed by Moes (Crit. Rev. Ther. Drug Carrier Syst., 10, 143 (1993)) and Deshpande el al (Drug Devel. Ind. Pharm., 22, 531 (1996)). Proposed methods described in these review articles for prolonging the gastric residence time of drug delivery systems include agents such as fatty acids, pharmacological agents which delay the passage of material from the stomach to the small intestine, and devices such as unfolding polymer sheets and balloon hydrogels (Park, K. and Park, H., Proc. Int. Symp. Control. Rel. Bioact. Mater., 14, 41 (1987) and Cargill R., Caldwell, I. J., Engle, K., Fix, J. A., Porter, P. A., and Gardner, C. R., Pharm. Res., 5, 533, 1988). While the concept of using large single unit dosage forms for gastric retention is attractive at first sight, potential problems, including blockage of the oesophagus or small itesine in certain patient groups, are known to be associated.
A further way to retain a drug delivery system in the stomach for an extended time period is to administer a nondisintegrating tablet or capsule, of a size greater than about 7 mm, and less than 20 mm, together with a large meal. The nature processes of gastric motility ensure that a delivery system of this size does not normally exit from the stomach until the stomach is empty of food. Thereafter the delivery system is cleared into the intestine through the action of a physiological process known as the migrating myoelectric complex (Phase III activity). However, in many instances, where drug absorption is affected by food, it would be advantageous to dose therapeutic agents to an empty, fasted stomach.
In the case of local treatment of gastric disorders, it would also be beneficial to achieve close adherence of a drug delivery system to the mucosal surface of the stomach, once the stomach has been emptied of liquid/food. Previous attempts to achieve this effect have not been successful, and no beneficial increase in residence time in man has been reported. By "beneficial increase in residence time" in this context, we mean that the residence time in the stomach for patients in the fasted state is at least three times greater than that for a control solution formulation.
The use of bioadhesive polymers as gastroretentive materials has been well reviewed in the pharmaceutical literature and is the subject of patent applications (see, for example, Ch'ng, H. S., Park, H., Kelly, P., and Robinson, J. R., J. Pharm. Sci., 74, 399 (1985); Longer, M. A., Ch'ng, H. S., and Robinson, J. R., J. Pharm. Sci., 74, 406 (1985); and Gurney and Junginger (Eds.) Bioadhesion Possibilities and Future Trends, Wissenschafliche Verlaggeschelchaft (1990)).
Tablets and pellets with increased gastric retention and bioadhesive properties have been described in international patent application WO 94/00112. The specific use of microadherent formulations in the treatment of gastric disorders (including H. pylori) has been described in international patent application WO 92/18143. Natural gums, plant extracts, sucralfate, acrylic acid or methacrylic acid derivatives are suggested as means to give sustained release and/or prolonged retention in the stomach.
Controlled release mucoadhesive microgranules for the oral administration is of furosemide are described in U.S. Pat. No. 5,571,533. The granules are made from lipophilic excipients and are coated with mucoadhesive anionic polymers selected from the group: carbomer, polycarbophil, hydrodroxypropyl methyl cellulose, hydroxypropyl cellulose or admixtures thereof.
Moes (1993) (see reference above) reports that the use of bioadhesive polymers to modify gastrointestinal transit has been abandoned since such mucoadhesive polymers are not able to control or slow down significantly the gastrointestinal transit of solid delivery systems, such as pellets and tablets
Pellets and other single units with a high density have also been investigated for gastroretention in Bechgaard, H. and Ladefoged, K., J. Pharm. Pharmacol., 30, 690 (1978) and Clarke, G. M. Gastrointestinal Transit of Spherical Granules of Differing Size and Density, PhD Thesis (1989), University of London), but the approach has not led to significant advantage in man unless the specific gravity is greater than 2.0. The skilled person will appreciate that such a high density presents a considerable disadvantage in a conventional pharmaceutical product from the standpoint of processing and weight.
Low density (floating systems) in the form of pellets and tablets have also been reported (Babu et al, Pharmazie, 45, 268 (1990); Mazer et al, J. Pharm. Sci. 77, 647 (1988)). Whilst some small benefits can be demonstrated, such systems in their own right do not appear to provide extended periods of residence in the stomach. However, they do offer some protection against early and random gastric emptying, though, in order to do this, need to be administered immediately after a meal
Floating minicapsules, having a size 0.1 to 2 mm, containing sodium bicarbonate, and which are coated by conventional water soluble film coating agents are described in U.S. Pat. No. 4,106,120. Similar floating granules based on gas generation have been described in U.S. Pat. No. 4,844,905. Floating capsules have also been described in U.S. Pat. No. 5,198,229. Atyabi et al, (J. Control. Rel., 42, 105 (1996)) have described ion exchange systems containing bicarbonate that release CO.sub.2 on contact with hydrochloric acid in the stomach, which gas is then trapped within a semi-permeable membrane surrounding the beads. This causes the particles to float. A suitable coating agent is disclosed as being Eudragit RS. The particles may then be given with food, though testing the formulation in question under the rigorous conditions of a fasted stomach is not described in the document in question. Moreover, no drug was incorporated into the particles to provide a slow release.
Burton et al (J. Pharm. Pharmac., 47, 901 (1995)) studied gastroretention of an ion-exchange resin in the form of negatively charged fine particles in comparison with an aqueous solution in man. They found that the first 60 to 70% of the resin cleared at the same rate as an aqueous phase but the remaining 30 to 40% of the resin was retained for an extended period. All subjects were dosed after an overnight Neither drug loaded microspheres nor gastroretentive systems with controlled release properties are mentioned or suggested.
European patent application EP 635 261 describes coated microparticles with improved drug absorption which consist of dehydrated microparticles comprising a nucleus of a gellable hydrocolloid onto which is deposited a film of cationic polysaccharide. The microparticles described in this document promote the absorption of drugs from the intestine. Gastroretention is not mentioned (on the contrary, it is suggested that the microparticles may be contained in an enterically coated gelatin capsule to protect the particles until they enter the duodenum). Incorporated within the matrix of the microparticles of EP 635 261 is a pharmacologically-useful drug. The hydrocolloids are preferably agar, pectin, xanthan gum, guar gum, locust bean gum, hyaluronic acid, casein and water soluble salts of alginic acid. The procedure for obtaining the microspheres is characterised by a multi-step process in which a solution of the gellable hydrocolloid is added to a medium in which gelling of the hydrocolloid takes place (eg calcium chloride). The microparticles so formed are separated and suspended in a concentrated solution of the drug from which the drug diffuises into the microparticles The microparticles are then separated and suspended in a solution of cationic polysaccharide (such as diethylaminodextran) to effect deposition of the polysaccharide onto the surface of the spheres. After this, the covered spheres are separated, washed and dried. No indication is given as to how the drug is retained in the particle during these various processing stages. The use of a rate controlling membrane as part of the composition of the microparticle is not mentioned. Moreover, no mention is made of the preparation of microparticles by spray drying.
Chitosan microspheres and microcapsules have been described previously as drug carrier systems. A review has been published by Yao et al (J.M.S.--i Rev. Macromol. Chem. Phy., C35, 155 (1995)). In order to make such systems, chitosan is cross-linked with an agent such as glutaraldehyde. Chitosan microcapsules, produced via a complex coacervation process, are also known. Alginate is a suitable negatively charged agent which may interact with positively charged chitosan (see for example, Polk et al, J. Pharm. Sci. 83, 178 (1994)). Sustained release and floating granules based on chitosan have been described by Miyazaki et al, Chem. Pharm. Bull., 36, 4033 (1988) and Inouye et al, Drug Des. Deliv., 4, 55, 1989. However, the particles mentioned in these documents are large in size and do not contain a release rate modifying polymer.
Chitosan compositions for controlled and prolonged release of macromolecules have been described in U.S. Pat. No. 4,895,724. A porous matrix of chitosan is described, in which the macromolecule is dispersed It is stated that the chitosan may be crosslinked by various agents to include glutaraldehyde, glyoxal, epiclorohydrin and succinaldehyde The use of microspheres for bioadhesion or gastroretention is not suggested.
Chitosan microspheres have been described by others, for use in oral delivery, (Ohya et al, J. Microencaps., 10, 1 (1993); JP 5339149, EP 486 959, EP 392 487). However, such particles have not been prepared with a view to providing a controlled release effect.
In a recent international patent application (WO 93/21906) a range of bioadhesive polymers in the form of, or as coatings on, microcapsules containing drugs. is described. Chitosan is described as performing poorly in bioadhesive tests. Moreover, the method of preparation of the chitosan microparticles may have rendered them negatively charged.
Thus, in summary, it would be of benefit to provide a system for delivering drug to the stomach which possessed the following attributes:
a significant retention time in the fasted stomach of mammalian (e.g. human) subjects PA1 a high loading of water soluble and lipid soluble drugs PA1 a controlled release of such drugs over a period of time that is relevant to the clinical need (ie delivery of drug to the stomach, and/or enhanced drug uptake from an absorption window in the small intestine). PA1 the preparation of such a formulation using established pharmaceutical processing methods PA1 the use of materials in the preparation of such a formulation that are approved for use in foods or pharmaceuticals or of like regulatory status.
Other desirable attributes include: